title: Computational proteomics analysis of binding mechanisms and molecular signatures of the HIV-1 protease drugs.
abstract: OBJECTIVE
  Computational proteomics analysis of biomolecular interactions is proposed to determine molecular signatures of the HIV-1 protease inhibitors. A comparative microscopic analysis is conducted for a panel of inhibitors which exemplify a diversity of the HIV-1 PR binding mechanisms, from the active site inhibition to intervening with the protease folding and dimerization.
  
  
  METHODS
  Replica-exchange Monte Carlo simulations with the conformational ensembles of the HIV-1 PR dimer and monomer structures enable a molecular analysis underlying diversity of the HIV-1 PR binding mechanisms.
  
  
  RESULTS
  We have investigated the molecular basis underlying diversity of the HIV-1 PR binding mechanisms. The molecular basis of the HIV-1 PR active site and dimerization inhibition mechanisms has been analyzed for an active site tripeptide inhibitor and a tetrapeptide inhibitor, which can act as both a dimerization inhibitor and a competitive active site inhibitor. We have also simulated a structural mimicry mechanism of the HIV-1 PR folding inhibition and dimerization, according to which the folding inhibitor targets the conserved HIV-1 PR regions by mimicking the interaction network of the active dimer.
  
  
  CONCLUSIONS
  We have shown that binding interfaces of the studied dimerization and folding HIV-1 PR inhibitors may enable structural mimicry with the hot spot residues of the HIV-1 PR dimer. The proposed structural models of intervening with the HIV-1 PR dimerization and folding support the mechanism of structural mimicry, which may alleviate drug resistance effects.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy and Center for Bioinformatics, The University of Kansas, 2030 Becker Drive, Lawrence, KS 66047, USA. verk@ku.edu
authors.forename: Gennady
authors.initials: G
authors.lastname: Verkhivker
mesh_terms: D019281:Dimerization; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D008958:Models, Molecular; D009010:Monte Carlo Method; D017510:Protein Folding; D040901:Proteomics
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1